LCAT (lecithin cholesterol:acyltransferase) is an important plasma enzyme found predominantly on HDL containing particles responsible for the conversion of plasma cholesterol to esterified cholesterol. Esterified cholesterol becomes incorporated into the core of the HDL particle and is able to be transferred to other lipoproteins. The conversion of cholesterol from peripheral cells to HDL is thought to be the first step in reverse cholesterol transport. ApoA-I and apoA-II are the two major apolipoproteins associated with plasma HDL involved in the regulation and metabolism of HDL. Overexpression of human LCAT in mice leads to HDL elevation and an increase in esterified cholesterol which may be beneficial. In order to better understand the role of apoA-I and apoA-II in LCAT overexpression, kinetic studies were performed in normal and transgenic mice overexpressing human LCAT. Transgenic mice overexpressing the human LCAT gene at levels 11-fold higher than control mice (1ug/ml) have increased TC and HDL-C. To further investigate the potential role of human LCAT in modulating dietary responses, age/sex matched transgenic mice (male=7, female=8) and controls (male=14, female=13) were placed on a high cholesterol-fat diet for 21 days. Pre-diet lipid values (mg/dl) in control mice : TC=97 +/- 11, HDL= 72 +/- 10mg/dl and transgenic: TC=121 +/- 16mg/dl, HDL-C= 84 +/- 17mg/dl. Post diet lipid values in controls: TC= 290 +/- 55mg/dl, HDL-C=85 +/- 55mg/dl, and in transgenic: TC= 313 +/- 83mg/dl, HDL-C=115 +/- 27mg/dl. Thus, on the high fat diet transgenic mice had significantly higher (p<0.05) HDL-C as well as reduced TC/HDL ratios than controls, without differences in Tg, PL, CE, LCAT mass and activity. Mouse 125I-apoA-I and 131I-apoA-II kinetic studies were performed to investigate the underlying mechanisms by which LCAT overexpression leads to increased HDL levels. ApoA-I and apoA-II catabolism was delayed in transgenic (n=5) (FCR=1.9 and 3.4d-1) when compared to control (FCR=2.6 and 4.2d-1). Our studies indicate that transgenic mice overexpressing human LCAT have a higher HDL-C and reduced IDL/LDL-C than controls. ApoA-I and apoA-II kinetic studies established delayed catabolism of HDL in transgenic mice resulting in increased HDL levels. On the high fat diet, human LCAT overexpression resulted in increased HDL-C, decreased IDL/LDL-C and decreased TC/HDL ratio, a lipoprotein phenotype associated with reduced risk of cardiovascular disease.